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`Pulmonary arterial hypertension in
`children
`
`A. Widlitz, R.J. Barst
`DOI: 10.1183/09031936.03.00088302 Published 1 January 2003
`
` Article
` Figures & Data
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`Info & Metrics
` PDF
`
`Abstract
`
`For physicians to admit that a group of patients remains for whom no cure is available in
`modern medicine is intellectually unsatisfying. Pulmonary arterial hypertension is a rare
`condition. Because the symptoms are nonspecific and the physical finding can be subtle, the
`disease is often diagnosed in its later stages. The natural history of pulmonary arterial
`hypertension is usually progressive and fatal.
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`At the 1998 Primary Pulmonary Hypertension World Symposium, clinical scientists from
`around the world gathered to review and discuss the future of pulmonary arterial
`hypertension. Bringing together experts from a variety of disciplines provided the opportunity
`for a better understanding of the pathology, pathobiology, risk factors, genetics, diagnosis and
`treatment for pulmonary arterial hypertension.
`
`Remarkable progress has been made in the field of pulmonary arterial hypertension over the
`past several decades. The pathology is now better defined and significant advances have
`occurred in understanding the pathobiological mechanisms. Risk factors have been identified
`and the genetics have been characterised. Advances in technology allow earlier diagnosis as
`well as better assessment of disease severity. Therapeutic modalities such as new drugs, e.g.
`epoprostenol, treprostinil and bosentan, and surgical interventions, e.g. transplantation and
`blade septostomy, which were unavailable several decades ago, have had a significant impact
`on prognosis and outcome. Thus, despite the inability to really cure pulmonary arterial
`hypertension, therapeutic advances over the past two decades have resulted in significant
`improvements in the outcome for children with various forms of pulmonary arterial
`hypertension.
`
`This review of pulmonary arterial hypertension will highlight the key features of pulmonary
`hypertension in infants and children and the current understanding of pulmonary arterial
`hypertension with specific recommendations for current practice and future directions.
`
` paediatrics
` pulmonary arterial hypertension
` pulmonary heart disease
`
`Until recently the diagnosis of primary pulmonary hypertension was virtually a death
`sentence. This was particularly true for children, in whom the mean survival was <1 yr. This
`bleaker outlook for children compared to adults was underscored by the data in the Primary
`Pulmonary Hypertension National Institutes of Health Registry 1. In this Registry, the median
`survival for all of the 194 patients was 2.8 yrs, whereas it was only 10 months for children.
`Significant progress in the field of pulmonary hypertension has occurred over the past several
`decades. Advances in technology have also allowed a better diagnosis and assessment of the
`disease severity with treatment now available that improves quality of life and survival 2–4.
`Nevertheless, extrapolation from adults to children is not straightforward for at least several
`reasons: 1) the anticipated lifespan of children is longer; 2) children may have a more
`reactive pulmonary circulation raising the prospect of greater vasodilator responsiveness and
`better therapeutic outcomes 5; and 3) despite clinical and pathological studies suggesting
`increased vasoreactivity in children, before the advent of long-term
`vasodilator/antiproliferative therapy, the natural history remained significantly worse for
`children compared to adult patients 1, 6.
`
`Definition and classification
`
`The definition of primary pulmonary hypertension in children is the same as for adult
`patients. It is defined as a mean pulmonary artery pressure ≥25 mmHg at rest or ≥30 mmHg
`during exercise, with a normal pulmonary artery wedge pressure and the absence of related or
`associated conditions. The inclusion of exercise haemodynamic abnormalities in the
`definition of pulmonary arterial hypertension is important since children with pulmonary
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`arterial hypertension often have an exaggerated response of the pulmonary vascular bed to
`exercise as well as in response to hypoventilation compared with adults. Not uncommonly,
`children with a history of recurrent exertional or nocturnal syncope have a resting mean
`pulmonary artery pressure of only ∼25 mmHg that markedly increases with modest systemic
`arterial oxygen desaturation during sleep, as well as with exercise.
`
`In 1998, at the Primary Pulmonary Hypertension World Symposium, clinical scientists from
`around the world proposed a new diagnostic classification system (table 1⇓). This
`classification system categorises pulmonary vascular disease by common clinical features.
`This classification reflects the recent advances in the understanding of pulmonary
`hypertensive diseases as well as recognising the similarity between primary pulmonary
`hypertension and pulmonary hypertension of certain other causes. Thus, in addition to
`primary pulmonary hypertension (both sporadic and familial), pulmonary arterial
`hypertension related to the following: congenital systemic to pulmonary shunts; collagen
`vascular disease; portal hypertension; human immunodeficiency virus infection; drugs and
`toxins (including anorexigens); and persistent pulmonary hypertension of the newborn, is
`classified with primary pulmonary hypertension as pulmonary arterial hypertension. This
`classification separates these cases of pulmonary arterial hypertension from pulmonary
`venous hypertension, pulmonary hypertension associated with disorders of the respiratory
`system and/or hypoxaemia, pulmonary hypertension due to chronic thrombotic and/or
`embolic disease, as well as pulmonary hypertension due to disorders directly affecting the
`pulmonary vasculature. This new diagnostic classification provides rationale for considering
`many of the therapeutic modalities that have been demonstrated to be efficacious for primary
`pulmonary hypertension for children who have pulmonary arterial hypertension related to
`these other conditions. Because the cause(s) of primary pulmonary hypertension, as well as
`pulmonary arterial hypertension related to other conditions, remains unknown or at least
`incompletely understood, the various treatment modalities used for pulmonary arterial
`hypertension have been based on the pathology and pathobiology of the pulmonary vascular
`bed. The pathology remains central to the understanding of the pathobiological mechanisms.
`As insight is advanced into the mechanisms responsible for the development of pulmonary
`arterial hypertension, the introduction of novel therapeutic modalities (alone and in
`combination) will hopefully increase the overall efficacy of therapeutic interventions for
`pulmonary arterial hypertension.
`
`Persistent pulmonary hypertension of the newborn is a syndrome characterised by increased
`pulmonary vascular resistance, right-to-left shunting and severe hypoxaemia 7. Persistent
`pulmonary hypertension of the newborn is frequently associated with pulmonary
`parenchymal abnormalities including meconium aspiration, pneumonia or sepsis, as well as
`occurring when there is pulmonary hypoplasia, maladaptation of the pulmonary vascular bed
`postnatally as a result of perinatal stress or maladaptation of the pulmonary vascular bed in
`utero from unknown causes. In some instances there is no evidence of pulmonary
`parenchymal disease and the ―injury‖ that is the ―trigger‖ of the pulmonary hypertension is
`unknown. Persistent pulmonary hypertension of the newborn is almost always transient 8,
`with infants either recovering completely without requiring chronic medical therapy or dying
`during the neonatal period despite maximal cardiopulmonary therapeutic interventions. In
`contrast, patients with pulmonary arterial hypertension who respond to medical therapy
`appear to need treatment indefinitely. Some infants with persistent pulmonary hypertension
`of the newborn may have a genetic predisposition to hyperreact to pulmonary
`vasoconstrictive ―triggers‖ such as alveolar hypoxia. It is possible that in some neonates the
`pulmonary vascular resistance may not fall normally after birth, although the diagnosis of
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`persistent pulmonary hypertension of the newborn is not made during the neonatal period and
`subsequently pulmonary hypertension is diagnosed as the pulmonary vascular disease
`progresses. Pathological studies examining the elastic pattern of the main pulmonary artery 9,
`10 suggest that primary pulmonary hypertension is present from birth in some patients,
`although it is acquired later in life in others.
`
`Whether pulmonary hypertension is due to increased flow or resistance (table 2⇓) depends on
`the cause of the pulmonary hypertension (table 3⇓). By definition, hyperkinetic pulmonary
`hypertension refers to pulmonary arterial hypertension from congenital systemic to
`pulmonary communications with increased pulmonary blood flow, e.g. ventricular septal
`defect or patent ductus arteriosus. Pulmonary venous hypertension is caused by disorders of
`left heart filling, e.g. mitral stenosis, pulmonary venous obstruction or left ventricular failure.
`Unless left heart obstruction or dysfunction is causing pulmonary venous hypertension, the
`pulmonary arterial wedge pressure is normal. Pulmonary vascular disease related to
`congenital heart disease (Eisenmenger's syndrome) is thought to develop after a hyperkinetic
`period of normal pulmonary vascular resistance and increased pulmonary blood flow. With
`pulmonary venous hypertension, as seen with mitral stenosis or left ventricular dysfunction,
`pulmonary artery pressure may vary from one child to another with the same elevations of
`pulmonary venous pressure accounted for by differences in pulmonary arterial vasoreactivity.
`Many different congenital heart defects are associated with an increased risk for the
`development of pulmonary vascular disease. Approximately one-third of patients with
`uncorrected congenital heart disease will die from pulmonary vascular disease 11. It is not
`known why some children with the same underlying congenital heart defect develop
`irreversible pulmonary vascular obstructive disease in the first year of life and others
`maintain ―operable‖ levels of pulmonary hypertension into the second decade and beyond. In
`many children whose congenital heart disease is diagnosed late in life, an important and
`difficult decision is necessary to determine whether the patient is ―operable‖ or has
`―irreversible‖ pulmonary vascular disease. In the past, this evaluation of operability has used
`anatomical criteria based on microscopic findings from lung biopsies to aid in the
`determination 12. More recently, new approaches to the evaluation of operability and
`perioperative management have allowed for surgical ―corrections‖ in patients who present
`late in life with elevated pulmonary vascular resistance. The assessment of surgical
`operability requires an accurate determination of the degree of pulmonary vasoreactivity or
`reversibility. It is important to predict whether the elevated pulmonary vascular resistance
`will respond favourably to pharmacological vasodilatation. In the past several years, studies
`with inhaled nitric oxide and intravenous epoprostenol have proven useful in the preoperative
`evaluations, as well as in the treatment of postoperative patients with elevated pulmonary
`vascular resistance 13–19. If a patient with elevated pulmonary vascular resistance is being
`considered for surgery there is an increased risk of postoperative pulmonary hypertensive
`crises. Thus, knowing if the pulmonary circulation will respond favourably to inhaled nitric
`oxide or intravenous prostacyclin will help in guiding the management of this potentially life-
`threatening complication 14, 20.
`
`Although misalignment of the pulmonary veins with alveolar capillary dysplasia is often
`diagnosed as persistent pulmonary hypertension of the newborn, it is a separate entity, i.e. a
`rare disorder of pulmonary vascular development that most often is diagnosed only after an
`infant has died from fulminant pulmonary hypertension 21. Features that will often alert
`clinicians to the possibility of alveolar capillary dysplasia include association with other
`nonlethal congenital malformations, the late onset of presentation (especially after 12 h) and
`severe hypoxaemia refractory to medical therapy. Infants most often present with severe
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`pulmonary arterial hypertension with transient responses to inhaled nitric oxide, which
`subsequently require increases in the dose of inhaled nitric oxide as well as transient
`responses after intravenous epoprostenol is added to the inhaled nitric oxide, with virtually all
`infants subsequently dying within the first several weeks of life. The only case with longer
`survival that the authors are aware of was an infant who presented at 6 months of age with
`what was initially thought to be overwhelming pneumonia requiring maximal
`cardiopulmonary support, including extracorporeal membrane oxygenation. The infant was
`initially diagnosed as having primary pulmonary hypertension, although upon further review
`of the open lung biopsy, alveolar capillary dysplasia was diagnosed with a very
`heterogeneous appearance on the biopsy. The infant significantly improved with inhaled
`nitric oxide and intravenous epoprostenol while awaiting heart-lung transplantation; she was
`subsequently weaned off extracorporeal membrane oxygenation as well as off mechanical
`ventilation and inhaled nitric oxide. She had marked clinical and haemodynamic
`improvement on chronic intravenous epoprostenol and continued chronic intravenous
`epoprostenol until she was nearly 4 yrs of age, at which time after acquiring a respiratory
`tract infection she rapidly deteriorated and died (unpublished data). Post-mortem examination
`confirmed the diagnosis of alveolar capillary dysplasia with a very heterogeneous
`involvement in the pulmonary parenchyma (consistent with the late presentation as well as
`significant palliative response with intravenous epoprostenol). This variability in clinical
`severity and histopathology is consistent with the marked biological variability that occurs in
`many forms of pulmonary arterial hypertension. When pulmonary hypertension results from
`neonatal lung disease such as meconium aspiration, the pulmonary vascular changes are most
`severe in the regions of the lung showing the greatest parenchymal damage.
`
`Congenital heart disease is the most common cause of pulmonary venous hypertension in
`children due to total anomalous pulmonary venous return with obstruction, left heart
`obstruction or severe left ventricular failure. The lungs of those born with left inflow
`obstruction show pronounced thickening in the walls of both the arteries and the veins; and
`the outcome depends on the results of the surgical intervention. Pulmonary veno-occlusive
`disease has a distinct pathological feature of uniform fibrotic occlusion of peripheral small
`venules 22. Although rare, it does occur early in childhood and has been reported in familial
`cases 23. Progressive long-segment pulmonary vein hypoplasia leading to pulmonary venous
`atresia is another uniformly fatal condition presenting in infancy with severe pulmonary
`venous hypertension.
`
`Epidemiology
`
`The frequency of pulmonary arterial hypertension in children as well as in adults remains
`unknown. Estimates of the incidence of primary pulmonary hypertension ranges from one to
`two new cases per million people in the general population 24. Although the disease is rare,
`increasingly frequent reports of confirmed cases suggest that more patients (both children and
`adults) have pulmonary arterial hypertension than had been previously recognised. On
`occasion, infants who have died with the presumed diagnosis of sudden infant death
`syndrome have had primary pulmonary hypertension diagnosed at the time of post-mortem
`examination. The sex incidence in adult patients with primary pulmonary hypertension is
`∼1.7:1 females:males 25, similar to the current authors' experience with children, 1.8:1 with
`no significant difference in the younger children compared with the older children.
`
`Natural history
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`Primary pulmonary hypertension historically exhibited a course of relentless deterioration
`and early death. Unfortunately, the data available for children is much less than for adult
`patients (due to the decreased occurrence of primary pulmonary hypertension in children
`compared with adults). Several large survival studies of primarily adult patients with primary
`pulmonary hypertension conducted in the 1980s have provided a basis of comparison for
`subsequent evolving therapeutic modalities. These retrospective and prospective studies have
`yielded quite uniform results: adult patients with primary pulmonary hypertension who have
`not undergone lung or heart/lung transplantation have had actuarial survival rates at 1, 3 and
`5 yrs of 68–77, 40–56 and 22–38%, respectively 1, 26–28. However, there is significant
`biological variability in the natural history of the disease in both adults and children, with
`some patients having a rapidly progressive downhill course resulting in death within several
`weeks after diagnosis as well as instances of survival for at least several decades.
`
`Pathobiology
`
`By definition, the aetiology(ies) of primary pulmonary hypertension are unknown, e.g.
`primary pulmonary hypertension is also referred to as ―unexplained‖ or ―idiopathic‖
`pulmonary hypertension. In young children, the pathobiology suggests failure of the neonatal
`vasculature to open and a striking reduction in arterial number. In older children, intimal
`hyperplasia and occlusive changes are found in the pulmonary arterioles as well as plexiform
`lesions. Despite significant advances (during the past several decades) in the understanding of
`the pathobiology of primary pulmonary hypertension, the mechanism(s) which initiate and
`perpetuate the disease process remain(s) speculative. Adults with primary pulmonary
`hypertension often have severe plexiform lesions and what appears to be ―fixed‖ pulmonary
`vascular changes. In contrast, children with primary pulmonary hypertension have more
`pulmonary vascular medial hypertrophy and less intimal fibrosis and fewer plexiform lesions.
`In the classic studies by Wagenvoort and Wagenvoort 29 in 1970, medial hypertrophy was
`severe in patients <15 yrs of age and it was usually the only change seen in infants. Among
`the 11 children <1 yr of age, all had severe medial hypertrophy, yet only three had intimal
`fibrosis, two with minimal intimal fibrosis and one with moderate intimal fibrosis and none
`had plexiform lesions. With increasing age, intimal fibrosis and plexiform lesions were seen
`more frequently. These post-mortem studies suggested that pulmonary vasoconstriction,
`leading to medial hypertrophy, may occur early in the course of the disease and may precede
`the development of plexiform lesions and other fixed pulmonary vascular changes (at least in
`some children). Furthermore, these observations may offer clues to the observed differences
`in the natural history and factors influencing survival in children with primary pulmonary
`hypertension compared with adult patients. Younger children in general appear to have a
`more reactive pulmonary vascular bed relative to both active pulmonary vasodilatation as
`well as pulmonary vasoconstriction, with severe acute pulmonary hypertensive crises
`occurring in response to pulmonary vasoconstrictor ―triggers‖ more often than in older
`children or adults. Thus, based on these early pathological studies, the most widely proposed
`mechanism for primary pulmonary hypertension until the late 1980s and early 1990s was
`pulmonary vasoconstriction 5, 30–32. Subsequent studies have identified potentially
`important structural and functional abnormalities; whether these perturbations are a cause or
`consequence of the disease process remains to be elucidated. These abnormalities include
`imbalances between vasodilator/antiproliferative and vasoconstrictive/mitogenic mediators,
`defects in the potassium channels of pulmonary artery smooth muscle cells and increased
`synthesis of inflammatory mediators which cause vasoconstriction as well as enhanced cell
`growth (fig. 1⇓) 33–40.
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`The molecular process(es) behind the complex vascular changes associated with primary
`pulmonary hypertension include the following: the description of phenotypical changes in
`endothelial and smooth muscle cells in hypertensive pulmonary arteries, the recognition that
`cell proliferation contributes to the structural changes associated with the initiation and
`progression of primary pulmonary hypertension (as well as apoptosis contributing to
`hypertensive pulmonary vascular disease) and the role of matrix proteins and matrix turnover
`in vascular remodelling and the importance of haemodynamic influences on the disease
`process. It is now clear that gene expression in pulmonary vascular cells responds to
`environmental factors, growth factors, receptors, signalling pathways and genetic influences,
`which can interact with each other. Examples of effector systems controlled by gene
`expression include the following: transmembrane transporters, ion channels, transcription
`factors, modulators of apoptosis, kinases, cell-to-cell interactive factors, e.g. intergrins and
`membrane receptors, mechanotransducers, extracellular matrix turnover and growth
`factors/cytokines and chemokine networks. By identifying causes of molecular process(es)
`that are linked to epidemiological risk factors, as well as developing molecular, biochemical
`and physiological tests to monitor and diagnose primary pulmonary hypertension, novel
`treatment strategies based on established pathobiological mechanisms will increase the
`overall efficacy of therapeutic interventions for primary pulmonary hypertension. Although
`many important physiological processes have been identified from descriptive studies from
`patients (suggesting possible pathobiological mechanisms in the development of primary
`pulmonary hypertension, fig. 2⇓), whether these observations are a cause or a consequence of
`the disease remains unclear.
`
`The vascular endothelium, an important source of locally active mediators that contribute to
`the control of vasomotor tone and structural remodelling, appears to play a crucial role in the
`pathogenesis of primary pulmonary hypertension 42. A number of studies have suggested
`that imbalances in the production or metabolism of several vasoactive mediators produced in
`the lungs may be important in the pathogenesis of primary pulmonary hypertension. An
`imbalance may exist in the vasoconstricting and vasodilator mediators as well as substances
`involving control of pulmonary vascular tone. These include increased thromboxane and
`decreased prostacyclin 33, 34, increased endothelin and decreased nitric oxide 35–37, 40, as
`well as other vasoactive substances yet to be described. Thromboxane and endothelin are
`vasoconstrictors as well as mitogens; in contrast, prostacyclin and nitric oxide are
`vasodilators with antiproliferative effects. Other factors may also be involved such as
`serotonin, platelet derived growth factor, angiotensin or the loss of pulmonary vascular
`prostacyclin or nitric oxide synthase gene expression. Vasoconstrictors may also serve as
`factors or cofactors that stimulate smooth muscle growth or matrix elaboration. It appears
`likely that endothelial injury results in the release of chemotactic agents leading to migration
`of smooth muscle cells into the vascular wall. In addition, this endothelial injury, coupled
`with excessive release of vasoactive mediators locally, promotes a procoagulant state, leading
`to further vascular obstruction. The process is characterised, therefore, by an inexorable cycle
`of endothelial dysfunction leading to the release of vasoconstrictive and vasoproliferative
`substances, ultimately progressing to vascular remodelling and progressive vascular
`obstruction and obliteration. In addition, defects in the potassium channels of pulmonary
`resistance smooth muscles may also be involved in the initiation and/or progression of
`primary pulmonary hypertension; inhibition of the voltage regulated (Kv) potassium channel
`has been reported in pulmonary artery smooth muscle cells from patients with primary
`pulmonary hypertension 43. Whether a genetic defect related to potassium channels in the
`lung vessels in primary pulmonary hypertension patients leading to vasoconstriction is
`relevant to the development of primary pulmonary hypertension in some patients remains
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`unknown. However, these studies suggest that primary pulmonary hypertension is a disease
`of ―predisposed‖ individuals, in whom various ―stimuli‖ may initiate the pulmonary vascular
`disease process. Whether or not vasoconstriction is the initiating event in the pathobiology of
`primary pulmonary hypertension, it is an important component in the pathophysiology of the
`disease (in at least a subset of patients). There may also be subsets of patients in whom
`endothelial dysfunction is the initiating ―injury‖ as opposed to vasoconstriction. Regardless,
`pulmonary vasoconstriction is an exacerbating factor in the disease progression. Exaggerated
`episodes of pulmonary vasoconstriction in susceptible individuals can damage the pulmonary
`vascular endothelium, resulting in further alterations in the balance between vasoactive
`mediators. Coagulation abnormalities may also occur, initiating or further exacerbating the
`pulmonary vascular disease 44, 45. The interactions between the humoral and cellular
`elements of the blood on an injured endothelial cell surface result in remodelling of the
`pulmonary vascular bed and contribute to the process of pulmonary vascular injury 46, 47.
`
`Migration of smooth muscle cells in the pulmonary arterioles occurs as a release of
`chemotactic agents from injured pulmonary endothelial cells 48. Endothelial cell damage can
`also result in thrombosis in situ, transforming the pulmonary vascular bed from its usual
`anticoagulant state (owing to the release of prostacyclin and plasminogen activator inhibitors)
`to a procoagulant state 49. Elevated fibrinopeptide-A levels in primary pulmonary
`hypertension patients also suggests that in situ thrombosis is occurring 50. Further support for
`the role of coagulation abnormalities at the endothelial cell surface comes from the reports of
`improved survival in patients treated with chronic anticoagulation 2, 26, 51.
`
`Pathophysiology
`
`Although the histopathology in children with primary pulmonary hypertension is often
`qualitatively the same as that seen with adult patients, the clinical presentation, natural
`history and factors influencing survival may differ. These differences appear to be most
`apparent in the youngest children. Children also appear to have differences in their
`hemodynamics parameters at the time of diagnosis compared with adult patients 52. The
`increased cardiac index in children (as opposed to adults) may reflect an earlier diagnosis and
`why children tend to have a greater acute vasodilator response rate with acute vasodilator
`testing than adults. The findings of higher heart rates and lower systemic arterial pressures in
`children is not unexpected. In order to understand the signs and symptoms of pulmonary
`arterial hypertension, one must first briefly review normal physiology of the pulmonary
`circulation. The pulmonary vascular bed normally has a remarkable capacity to dilate and
`recruit unused vasculature to accommodate increases in blood flow. In pulmonary arterial
`hypertension, however, this capacity is lost, leading to increases in pulmonary artery pressure
`at rest and further elevations in pulmonary artery pressure with exercise. In response to this
`increased afterload, the right ventricle hypertrophies. Initially, the right ventricle is capable of
`sustaining normal cardiac output at rest, but the ability to increase cardiac output with
`exercise is impaired. As pulmonary vascular disease progresses, the right ventricle fails and
`resting cardiac output decreases. As right ventricular dysfunction progresses, right ventricular
`diastolic pressure increases and evidence of right ventricular failure, the most ominous sign
`of pulmonary vascular disease, manifests. Although the left ventricle is not directly affected
`by the pulmonary vascular disease, progressive right ventricular dilatation can impair left
`ventricular filling, leading to moderately increased left ventricular end diastolic and
`pulmonary capillary wedge pressures. Dyspnoea, the most frequent presenting complaint in
`adults with primary pulmonary hypertension as well as in some children with primary
`pulmonary hypertension, is due to impaired oxygen delivery during physical activity as a
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`result of an inability to increase cardiac output in the presence of increased oxygen demands.
`Syncopal episodes, which occur more frequently with children than with adults, are often
`exertional or postexertional, and imply a severely limited cardiac output, leading to
`diminished cerebral blood flow. Peripheral vasodilatation during physical exertion can
`exacerbate this condition.
`
`From the pathobiology and pathophysiology of primary pulmonary hypertension, the two
`most frequent mechanisms of death are progressive right ventricular failure and sudden death,
`with the former occurring far more often 1. With progressive right ventricular failure, the
`scenario, described above, leads to dyspnoea, hypoxaemia and a progressive decrease in
`cardiac output. Pneumonia may be fatal as a result of alveolar hypoxia causing further
`pulmonary vasoconstriction and an inability to maintain adequate cardiac output, resulting in
`cardiogenic shock and death. When arterial hypoxaemia and acidosis occur, life-threatening
`arrhythmias may develop. Postulated mechanisms for sudden death include brady- and
`tachyarrhythmias, acute pulmonary emboli, massive pulmonary haemorrhage and sudden
`right ventricular ischaemia. Haemoptysis appears to be due to pulmonary infarcts with
`secondary arterial thromboses.
`
`Diagnosis and assessment
`
`Although the diagnosis of primary pulmonary hypertension is one of exclusion, it can be
`made with a high degree of accuracy if care is taken to exclude all likely related or associated
`conditions. A thorough and detailed history and physical examination, as well as appropriate
`tests, must be performed to uncover potential causative or contributing factors, many of
`which may not be readily apparent. Questions should be asked about family history:
`pulmonary hypertension, connective tissue disorders, congenital heart disease, other
`congenital anomalies, and early unexplained deaths. If the family history suggests familial
`primary pulmonary hypertension, careful screening of all family members is recommended. It
`is reasonable to consider a transthoracic echocardiogram in all first degree relatives of the
`patient diagnosed with primary pulmonary hypertension (at the time of his/her diagnosis), as
`well as at any time symptoms consistent with pulmonary arterial hypertension occur, and
`subsequently every 3–5 yrs in asymptomatic family members (per the World Health
`Organization (WHO) World Symposium on Primary Pulmonary Hypertension
`recommendations 1998) 53. Although it is reasonable to believe that initiating therapy in
`―asymptomatic‖ siblings with familial primary pulmonary hypertension may improve
`outcome, this remains to be proven. Additional issues to address include a carefully detailed
`birth and neonatal history, a detailed drug history, prolonged medication history including
`psychotropic drugs and appetite suppressants, exposure to high altitude or to toxic cooking oil
`54, 55, travel history and any history of frequent respiratory tract infections. Problems with
`coagulation should also be queried. The answers to these questions may offer clues to a
`possible ―trigger‖ or the ―injury‖ initiating the development of the pulmonary arterial
`hypertension.
`
`The diagnostic evaluation in children suspected of having primary pulmonary hypertension is
`similar to that of adult